Macromolecular drug transport into the brain using targeted therapy

Abstract

The brain forms a vascular barrier system comprised of the blood-brain barrier (BBB) and the blood-CSF barriers. Together they prevent the passage of a number of drugs from the bloodstream into the brain parenchyma, because their molecules are either hydrophilic, too large or both. In many disorders affecting the CNS, these barriers are physically intact, which limits the entry of large molecules with potentially important therapeutic implications. The BBB is the most relevant barrier against drug delivery to the brain as the area of the BBB is about 1000 times larger than that of the blood-CSF barrier. Moreover, the transport through the choroid plexus is directed to the ventricular system, only allowing the transported molecules to access cells near the ventricular and subarachnoid surfaces. This review outlines possible routes for targeted entry of macromolecules like polypeptides, siRNA and cDNA. In the vascular compartment, targeting molecules should interact specifically with proteins expressed exclusively by these barrier cells, and therefore prevent uptake elsewhere in the body. Preferably, the targeting molecule should be conjugated to a drug carrier that allows uptake of a defined cargo. However, evidence for transport of such targetable drug-carrier complexes through the barriers, in particular the BBB, is contentious, and is discussed with emphasis on the different attempts that have evinced transport through the BBB not only from blood-to-endothelium, but also from endothelium-to-brain.

Uptake and Transport of Superparamagnetic Iron Oxide Nanoparticles through Human Brain Capillary Endothelial Cells

“…A p value of <0.05 was considered statistically significant. (1) The inserts were moved from well plates containing astrocytes cultured a remote distance from the endothelial cells (2) to empty well plates (3). After addition of the nanoparticles (4), the endothelial cells were incubated for 24 h. The medium from the inserts was then changed, and the inserts were washed three times with PBS to remove nanoparticles that had not been taken up by the BCECs (5 and 6).…”

“…Even molecules with these properties have only limited success in crossing the BBB and entering the brain. 3 Many different colloidal drug carriers have been created, e.g., liposomes or polyplexes, which fulfill the demands of being at the nanosize scale. These drug carriers have a hydrophilic outward surface that allows them to circulate in blood plasma.…”

In vivo Functional Evaluation of Increased Brain Delivery of the Opioid Peptide DAMGO by Glutathione-PEGylated Liposomes

“…The mechanism of this increase is, however, unknown. Also among other promising carrier candidates, the main transport mechanism has been widely debated (9,10). Receptor-mediated and adsorptive-mediated transport of the nanocarrier and its cargo, blockage of efflux transporters, or disruption of the BBB as a result of toxic effects have all been suggested as possible mechanisms of action for enhanced delivery to the brain, when using different nanocarriers.…”

Delivery of Peptides and Proteins to the Brain Using Nano-Drug Delivery Systems and Other Formulations

“…In certain regions of the brain (circumventricular organs, CVO) capillaries are leaky and neuronal projections have direct access to solutes of the plasma. Reprinted from [ 70 ] with permission from John Wiley and Sons. B. Morphology of the blood-brain barrier (BBB) that is formed by the brain capillary endothelium, pericytes and astrocytes and strengthened by the tight junctions between the endothelial cells.…”